Small amounts of 3H-leucine were injected into discrete regions in the rostral medulla of the cat. Descending projections from these sites were studied with autoradiographic methods. On the basis of differential projections to the medulla and spinal cord, three distinct regions were delineated. Nucleus reticularis gigantocellularis (Rgc), located dorsally in the medullary reticular formation, projects primarily to “motor” related sites, including cranial motor nuclei VI, VII, XII, nucleus intercalatus, and a part of the ipsilateral medial accessory olive. The projection to the spinal cord is primarily via the ipsilateral ventrolateral and contralateral ventral funiculi. The Rgc terminal field is in lamina VII and VIII ipsilateral and lamina VIII contralateral to the injection site. In contrast, nucleus raphe magnus, (NRM) located ventrally, in the midline of the rostral medulla projects primarily to structures with known nociceptive and/or visceral afferent input. These sites include the solitary nucleus, the dorsal motor nucleus (X) and the marginal and gelatinous layers of the spinal trigeminal nucleus caudalis. The projection to the spinal cord is bilateral, via the dorsolateral funiculus. Terminal fields are found in the marginal zone and the substantia gelatinosa of the dorsal horn, and more deeply in lamina V, medial VI and VII. Nucleus reticularis magnocellularis (Rmc), located lateral to NRM and ventral to Rgc, has an overlapping projection with NRM, but the projection is ipsilateral. This difference between Rmc and Rgc is correlated with cytoarchitectural features of the two regions. The possibility that the raphe-spinal pathway in the DLF mediates opiate and brain stimulation-produced analgesia is discussed.

Three bulbospinal pathways from the rostral medulla of the cat: an autoradiographic study of pain modulating systems.

There is considerable evidence that the dorsolateral funiculus (DLF) of the spinal cord contains descending pathways critical for both opiate and brainstem stimulation-produced analgesia. To obtain a comprehensive map of brainstem neurons projecting to the spinal cord via the DLF, large injections of horseradish peroxidase (HRP) were made into the lumbosacral spinal cord of cat and rat. These injections were made caudal to midthoracic lesions which spared only a single DLF or ventral quadrant (VQ); thus only those neurons whose axons descended in the spared funiculus would be labelled.

Cells with descending axons in the VQ were concentrated in the medullary nucleus raphe pallidus and obscurus, nucleus retroambiguus and in various subregions of the reticular formation including the nucleus reticularis ventralis, gigantocellularis, magnocellularis, pontis caudalis and pontis oralis. Significant numbers of neurons were also found in medial and lateral vestibular nuclei and in several presumed catecholamine-containing neurons of the dorsolateral pons. In the rat, but not in the cat, considerable numbers of cells are present in the mesencephalic reticular formation, just lateral to the periaqueductal gray. In both species, some cells were found in the paraventricular nucleus of the hypothalamus.

Brainstem cells projecting in the DLF were concentrated in the nucleus raphe magnus and in the adjacent nucleus reticularis magnocellularis, ipsilateral to the spared funiculus. Significant numbers of cells were found in the dorsolateral pons, differing somewhat in their distribution from those projecting in the VQ. DLF-projecting cells were also present in the ipsilateral Edinger-Westphal nucleus and periaqueductal grey contralateral red nucleus of the midbrain and in the ipsilateral hypothalamus. Smaller projections from other sites are described.

These results are discussed in terms of the differential contribution of several brainstem neuronal groups, including the serotonergic nucleus, raphe magnus, the ventromedial reticular formation of the medulla, and various catecholamine-containing neurons of the dorsolateral pontine tegmentum to the analgesia produced by opiates and electrical brain stimulation.

The origin of descending pathways in the dorsolateral funiculus of the spinal cord of the cat and rat: further studies on the anatomy of pain modulation.

The role of serotonin in reflex modulation and locomotor rhythm production in the mammalian spinal cord.

It has been suggested that drugs block the effects of serotonin (5-HT) in the brain based on (1) the ability to block the effects of 5-HT on smooth muscle and on invertebrate neurons (e.g., cinanserin, cyproheptadine, methysergide [UML], and metergoline [MCE]) and (2) the ability to block certain gross electrophysiological effects of 5-hydroxytryptophan (e.g., methiothepin). Although these “antagonists” are often assumed to block all 5-HT receptors in the CNS, the ability of these drugs to block 5-HT at documented 5-HT synapses in the brain has not been thoroughly tested. Since 5-HT may produce either excitation or inhibition, these antagonists were evaluated with respect to both types of responses. Only inhibition is produced by 5-HT on cells in areas receiving a heavy serotonergic input (e.g., ventral lateral geniculate, optic tectum and amygdala) as determined by fluorescent histochemistry. Raphe cells, virtually the only 5-HT-containing neurons in the CNS, are also inhibited by 5-HT. Cells in the reticular formation, an area which receives little or no 5-HT input may be either excited or inhibited by 5-HT. The five putative antagonists do not block the inhibitory response to 5-HT in any of these areas. The excitatory response to 5-HT in the reticular formation can be blocked by the putative antagonists. However, the failure of these compounds to block 5-HT in any of the three areas tested that receive a heavy serotonergic input casts doubt on the assumption that any one of these compounds is a universal central 5-HT antagonist.

Peripheral serotonin antagonists: failure to antagonize serotonin in brain areas receiving a prominent serotonergic input.

Opiate antagonist, naloxone, strongly reduces analgesia induced by stimulation of a raphe nucleus (centralis inferior)

Histochemical evidence suggests that neurons in the brain stem raphe nuclei which contain serotonin (5-HT) project to the spinal cord. Stimulation of the raphe nuclei facilitated and inhibited spinal reflexes: the conduction velocity calculated for the bulbospinal inhibitory pathway was 10 m/sec. Antagonists of 5-HT were without effect on facilitation, but readily blocked raphe-evoked inhibition of the monosynaptic reflex. The antagonists also blocked the inhibition evoked from the ventral medial reticular formation. Blockade of bulbospinal inhibition was observed after LSD (0.25 mg/kg), methysergide (0.5 mg/kg), BOL (1–1.5 mg/kg) and cinanserin (4 mg/kg) but not cyproheptadine (5 mg/kg). The 5-HT antagonists were more effective when injected into the arterial supply of the spinal cord than when injected into the arterial supply of the brain stem. Thus, the antagonists appear to act at the spinal level, presumably blocking the effect of a 5-HT-releasing interneuron intercalated in the bulbospinal inhibitory pathway.

E. G. Andeeson

Papers

The blockade of bulbospinal inhibition by 5-hydroxytryptamine antagonists.